Genomes and Genes
Aleksey G Kazantsev
Affiliation: Massachusetts General Hospital
- Central role of alpha-synuclein oligomers in neurodegeneration in Parkinson diseaseAleksey G Kazantsev
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Bldg 114, 3300 16th St, Charlestown, MA 02129 4404, USA
Arch Neurol 65:1577-81. 2008..Herein, we review the data supporting this concept, propose a scheme of events leading to synuclein-induced neuronal death, and discuss protein deacetylase sirtuins as new potential therapeutic targets involved in this process...
- Highlights of the Keystone Symposium: sirtuins in metabolism, aging and diseaseMichele M Maxwell
MassGeneral Institute for Neuodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, USA
EMBO Mol Med 4:557-60. 2012..It was a vibrant and lively meeting, and in the spirit of Keystone Symposia, both established sirtuin researchers and those new to the field enjoyed a unique opportunity to interact and exchange ideas...
- SIRT2 as a Therapeutic Target for Age-Related DisordersRita Machado de Oliveira
Cell and Molecular Neuroscience Unit, Instituto de Medicina Molecular Lisboa, Portugal
Front Pharmacol 3:82. 2012..This review summarizes the main scientific advances on SIRT2 protein biology and explores its potential as a therapeutic target for treatment of age-related disorders...
- Cellular pathways leading to neuronal dysfunction and degenerationAleksey G Kazantsev
Department of Neurology, Harvard Medical School, Disease, Massachusetts, USA
Drug News Perspect 20:501-9. 2007..Elucidation of the precise neurodegenerative mechanism(s) is essential for development of effective and safe therapy for these lethal human disorders...
- Drug targeting of dysregulated transcription in Huntington's diseaseAleksey G Kazantsev
Harvard Medical School, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129 4404, USA
Prog Neurobiol 83:249-59. 2007..In this chapter we review current progress in this area of therapeutic development. We also discuss possible drug discovery strategies targeting altered transcriptional pathways...
- Therapeutic application of histone deacetylase inhibitors for central nervous system disordersAleksey G Kazantsev
Harvard Medical School, Massachusetts General Hospital, Mass General Institute for Neurodegenerative Disease, Charlestown, Massachusetts 02129 4404, USA
Nat Rev Drug Discov 7:854-68. 2008....
- Discovery of a novel small-molecule targeting selective clearance of mutant huntingtin fragmentsMyra Coufal
Massachusetts Institute of Technology, Cambridge, MA, USA
J Biomol Screen 12:351-60. 2007..These compounds were subjected to a functional assay, which yielded a lead compound that rescues cells from induced mutant polyglutamine toxicity...
- Sirtuin 2 inhibitors rescue alpha-synuclein-mediated toxicity in models of Parkinson's diseaseTiago Fleming Outeiro
Alzheimer s Research Unit, MGH, Harvard Medical School, CNY 114, 16th Street, Charlestown, MA 02129, USA
Science 317:516-9. 2007..Furthermore, the inhibitors protected against dopaminergic cell death both in vitro and in a Drosophila model of Parkinson's disease. The results suggest a link between neurodegeneration and aging...
- The Sirtuin 2 microtubule deacetylase is an abundant neuronal protein that accumulates in the aging CNSMichele M Maxwell
MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Boston, MA 02115, USA
Hum Mol Genet 20:3986-96. 2011....
- Pharmacological inhibition of PARP-1 reduces alpha-synuclein- and MPP+-induced cytotoxicity in Parkinson's disease in vitro modelsTiago Fleming Outeiro
Department of Neurology, Harvard Medical School and MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Bldg 114 3300, 16th St, Charlestown, MA 02129 4404, USA
Biochem Biophys Res Commun 357:596-602. 2007..Further, our results suggest a rationale for the development of highly potent, bio-available, brain-penetrable PARP-1 inhibitors to provide therapeutic benefits for Parkinson's patients...
- The sirtuin 2 inhibitor AK-7 is neuroprotective in Huntington's disease mouse modelsVanita Chopra
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA 02129 4404, USA
Cell Rep 2:1492-7. 2012..Our results provide preclinical validation of SIRT2 inhibition as a potential therapeutic target for HD and support the further development of SIRT2 inhibitors for testing in humans...
- LBH589, A Hydroxamic Acid-Derived HDAC Inhibitor, is Neuroprotective in Mouse Models of Huntington's DiseaseVanita Chopra
Department of Neurology, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA, USA
J Huntingtons Dis 5:347-355. 2016..It has been difficult to translate these treatments to the clinic, however, because existing compounds have limited potency or brain bioavailability...
- SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease ModelsLuisa Quinti
Department of Neurology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA
Cell Chem Biol 23:849-61. 2016..These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders. ..
- The sirtuin-2 inhibitor AK7 is neuroprotective in models of Parkinson's disease but not amyotrophic lateral sclerosis and cerebral ischemiaXiqun Chen
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, 02129, United States of America
PLoS ONE 10:e0116919. 2015....
- Two approaches to drug discovery in SOD1-mediated ALSWendy J Broom
Day Neuromuscular Research Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA 02129, USA
J Biomol Screen 11:729-35. 2006..Ultimately, the authors believe that these 2 cell-based assays will provide powerful strategies to identify novel therapies for the treatment of inherited SOD1-associated forms of ALS...
- Discovery of bioactive small-molecule inhibitor of poly adp-ribose polymerase: implications for energy-deficient cellsStephen M Altmann
Massachusetts General Institute for Neurodegenerative Disease and Harvard Medical School, Department of Neurology, Massachusetts General Hospital, Charlestown, 02129, USA
Chem Biol 13:765-70. 2006..The protective role of PARP1 inhibitors against oxidative stress has been shown in this model system...
- RNA interference-mediated silencing of mutant superoxide dismutase rescues cyclosporin A-induced death in cultured neuroblastoma cellsMichele M Maxwell
Day Laboratory for Neuromuscular Research and High Throughput Screening Laboratory, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA 02129, USA
Proc Natl Acad Sci U S A 101:3178-83. 2004..The present study further supports the therapeutic potential of RNAi-based methods for the treatment of inherited human diseases, including ALS...
- A potent small molecule inhibits polyglutamine aggregation in Huntington's disease neurons and suppresses neurodegeneration in vivoXiaoqian Zhang
Department of Biochemistry, Boston University Medical School, Boston, MA 02118, USA
Proc Natl Acad Sci U S A 102:892-7. 2005..The aggregation inhibitors identified in this screen represent four primary chemical scaffolds and are strong lead compounds for the development of therapeutics for human polyQ diseases...
- Loss of huntingtin function complemented by small molecules acting as repressor element 1/neuron restrictive silencer element silencer modulatorsDorotea Rigamonti
Centre for Stem Cell Research and Department of Pharmacological Sciences, University of Milan, Via Balzaretti 9, Milan 20133, Italy
J Biol Chem 282:24554-62. 2007....
- Pharmacological promotion of inclusion formation: a therapeutic approach for Huntington's and Parkinson's diseasesRuth A Bodner
Center for Cancer Research, Massachusetts Institute of Technology, Room E18 505, 77 Massachusetts Avenue, Cambridge, MA 02139, USA
Proc Natl Acad Sci U S A 103:4246-51. 2006....
- New directions for neurodegenerative disease therapy: using chemical compounds to boost the formation of mutant protein inclusionsRuth A Bodner
Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA
Cell Cycle 5:1477-80. 2006..In this review, we discuss these results, and place them in the context of ongoing therapeutic discovery efforts for Huntington's disease and other neurodegenerative diseases...